Abstract
Introduction
Anxiety and depression are frequently associated with migraine, and antidepressant use can complicate treatment. These analyses assessed the safety and tolerability of rimegepant in participants with migraine and anxiety and/or depression, or using selective serotonin reuptake inhibitors (SSRIs) and/or other antidepressants.
Methods
Data were from a phase II/III safety study of rimegepant for the acute treatment of migraine. Participants with a history of 2–14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg as needed up to once daily for up to 52 weeks. These post hoc subgroup analyses assessed safety according to self-reported history of anxiety (yes or no) or depression (yes or no), and current use of SSRIs (yes or no) or other antidepressants (yes or no).
Results
Of 1800 treated participants, 23.2% (n = 417) had a self-reported history of anxiety, 23.7% (n = 426) had a self-reported history of depression, and 11.2% (n = 202) reported both anxiety and depression. A total of 10.1% (n = 181) of participants were using an SSRI, 10.8% (n = 195) were using other antidepressants, and 1.8% (n = 32) were using both. Across the subgroups with anxiety, without anxiety, with depression, without depression, using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively, similar proportions of participants reported adverse events (67.1%, 58.4%, 62.0%, 60.0%, 64.1%, 60.0%, 66.2%, 59.8%), serious adverse events (3.6%, 2.3%, 2.8%, 2.5%, 3.3%, 2.5%, 5.1%, 2.3%), and discontinuation of rimegepant due to adverse events (4.1%, 2.2%, 3.1%, 2.5%, 5.0%, 2.4%, 3.1%, 2.6%). Numerical improvements in a variety of participant-reported outcomes were also observed at weeks 12 and 52.
Conclusions
Rimegepant showed favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression and with SSRI and/or other antidepressant use.
Trial Registration
Clinicaltrials.gov: NCT03266588.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40122-024-00675-6.
Keywords: Anxiety, Calcitonin gene-related peptide receptor antagonist, Depression, Mental health, Migraine, Rimegepant
Plain Language Summary
People with migraine often have anxiety and depression, and the use of antidepressants can complicate the choice of migraine treatment. These analyses of a long-term, open-label, phase II/III study assessed the safety and tolerability of rimegepant in adults with migraine according to history of anxiety and/or depression, and the use of antidepressants. Rimegepant, when used as an acute treatment for migraine, was generally safe and well tolerated in adults with migraine and a history of anxiety and/or depression, and with antidepressant use.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40122-024-00675-6.
Key Summary Points
| Why carry out this study? |
| Anxiety and depression are frequently associated with migraine, and concomitant antidepressant use can complicate drug selection for migraine. |
| The small molecule calcitonin gene-related peptide receptor antagonist rimegepant is not expected to affect serotonin levels or interact with serotonin receptors. |
| These post hoc subgroup analyses of a long-term safety study assessed the safety of rimegepant according to self-reported history of anxiety (yes or no) or depression (yes or no), and current use of selective serotonin reuptake inhibitors (SSRIs; yes or no) or other antidepressants (yes or no). |
| What was learned from the study? |
| Across the subgroups with anxiety, without anxiety, with depression, without depression, using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, similar proportions of participants reported adverse events, serious adverse events, and discontinuation of rimegepant due to adverse events. |
| Rimegepant showed favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression, and with SSRI and/or other antidepressant use. |
Introduction
Migraine is associated with a variety of psychiatric comorbidities, including anxiety and depression [1, 2]. The relationships with both anxiety and depression are bidirectional [3], such that patients with migraine have higher incidences of anxiety and depression [4, 5], and anxiety and depression are also associated with increased risks of developing migraine [6] and chronicity of migraine [7]. Depression occurs in patients with migraine at almost twice the rate seen in the general population, and the prevalence of anxiety increases with migraine attack frequency [2]. In patients with migraine, comorbid anxiety and/or depression is associated with a reduction in quality of life, increased disability [8], and increased suicide risk [2, 9, 10]. Coexisting anxiety and depression is associated with even greater levels of disability [11], and perceived efficacy of and satisfaction with migraine therapies may be reduced [12]; as a result, migraine may be more difficult to treat in this population.
Patients with migraine and anxiety and/or depression might be taking antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors, norepinephrine dopamine reuptake inhibitors, and some with multimodal serotonergic effects. Concomitant antidepressant use can complicate drug selection for the acute treatment of migraine. Triptans and ditans are serotonin receptor agonists and consequently carry warnings for serotonin syndrome—particularly during coadministration with SSRIs, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors [13, 14]—although reports of serotonin syndrome are rare in clinical practice [15–17].
The small molecule calcitonin gene-related peptide (CGRP) receptor antagonist rimegepant is not expected to affect serotonin levels or interact with serotonin receptors. Rimegepant is indicated for the acute treatment of migraine with or without aura in adults and the preventive treatment of episodic migraine in adults. The efficacy and safety of rimegepant have been established in multiple randomized controlled trials for the acute treatment [18–21] and preventive treatment [22] of migraine.
Longer-term safety and tolerability of rimegepant for the acute treatment of migraine were investigated during open-label treatment of up to 52 weeks [23, 24]. The aim of the current post hoc subgroup analyses of that study was to assess safety in participants with a history of anxiety and/or depression, and during concurrent use of antidepressants.
Methods
Study Design
A prospective, phase II/III, 1-year, open-label safety study of rimegepant for the acute treatment of migraine (Study 201, NCT03266588) was conducted from August 30, 2017, to July 15, 2019, across 103 sites in the United States. After a screening visit and a 30-day observation period, participants commenced a long-term treatment period of up to 12 months. Study visits were approximately every 2 weeks during the first month and then every 4 weeks through the study, with a final follow-up visit 14 ± 2 days after the end of treatment. The full methodology for the study has been published previously [24].
The study was conducted in accordance with Good Clinical Practice, as defined by the International Conference on Harmonisation, Good Laboratory Practice, the Declaration of Helsinki, and all applicable regulations. Prior to the study, all participants provided written informed consent, and all investigators received Institutional Review Board approval for the protocol (Advarra IRB [IRB00000971], Schulman Associates IRB [IRB00007642; acquired by Advarra], and Biomedical Research Alliance New York [BRANY] IRB [IRB00000080]).
Participants
Adults (males and females ≥ 18 years of age) were eligible for inclusion if they had at least a 1-year history of migraine (with or without aura) consistent with a diagnosis according to the International Classification of Headache Disorders-3 (beta version) [25]. To be included, migraine onset had to be before the age of 50 years, participants had to have 2–14 migraine attacks of moderate or severe pain intensity per month (within the last 3 months prior to screening), and attacks lasted 4–72 h on average if untreated. Participants also had to be able to distinguish migraine attacks from tension or cluster headaches. Key exclusion criteria were major depressive disorder (current diagnosis, a major depressive episode within the last 12 months, or requiring treatment with atypical antipsychotics), and current diagnosis of schizophrenia, bipolar disorder, or borderline personality disorder. Individuals scoring > 0 on the Sheehan Suicidality Tracking Scale (S-STS) for the 30 days prior to screening were excluded. Participants with a history of depression or anxiety, including those receiving SSRIs or other antidepressants, could be enrolled at the investigator’s discretion. A history of basilar or hemiplegic migraine was excluded, as were other pain syndromes, psychiatric conditions, dementia, or significant neurologic disorders that might interfere with study assessments, cardiovascular disease (uncontrolled, unstable, or recently diagnosed), uncontrolled hypertension or diabetes, glycated hemoglobin (HbA1c) ≥ 6.5%, body mass index ≥ 30 kg/m2, and history of HIV disease.
Preventive treatments for migraine were allowed if the dose was stable and not likely to change. Concomitant use of atypical antipsychotics, including aripiprazole, olanzapine, quetiapine, ziprasidone, or risperidone, or valproic acid/valproate was prohibited during the long-term treatment period. Standard-of-care analgesics, including acetaminophen (up to 1000 mg/day) and nonsteroidal anti-inflammatory drugs, and anti-emetics could be taken if needed; however, use of triptans, ergotamine, and opioids was not permitted.
Intervention
Based on self-reported migraine history, participants were assigned to one of three nonrandomized treatment cohorts. Enrollment cohort 1 (PRN [as needed] 2–8) had a history of 2–8 moderate-to-severe attacks/month and enrollment cohort 2 (PRN 9–14) had a history of 9–14 moderate-to-severe attacks/month. Participants enrolled in these PRN cohorts were assigned to rimegepant 75 mg to be taken as needed up to once daily to treat migraine attacks of any severity, for up to 52 weeks. The protocol was amended to add enrollment cohort 3 (scheduled EOD [every other day] + PRN) and participants with a history of 4–14 moderate-to-severe attacks/month were assigned to rimegepant 75 mg to be taken every other day (irrespective of migraine attacks) and additionally as needed on other non-scheduled days to treat migraine attacks of any severity, up to once daily for up to 12 weeks. Rimegepant 75 mg oral tablets were supplied by Biohaven Pharmaceuticals.
Safety Outcomes
Primary endpoints were the frequency and severity of adverse events (AEs), frequencies of serious AEs (SAE), AEs leading to study drug discontinuation, and clinically significant blood test abnormalities. On-treatment AEs were those with start dates in the on-treatment safety analysis period, from the time after the first dose of rimegepant through the last dose of rimegepant + 7 days. The follow-up period was from the time following the last dose of rimegepant + 7 days. Prespecified suicidality AEs included the preferred terms completed suicide, suicide attempt, and suicidal ideation. Incidences of serotonin syndrome were detected retrospectively by review of preferred terms. Medical Dictionary for Regulatory Activities (MedDRA) version 21.1 was used. Blood samples were taken for liver function tests at baseline and during subsequent study visits. The S-STS [26, 27], a prospective self-reported or clinician-administered rating scale containing 16 questions to track treatment-emergent suicidal ideation and behaviors, was completed on paper at baseline and at each study visit; the protocol stipulated that any participant with a response > 0 to any question, excluding question 2, was to be immediately discontinued from the study.
Other Outcomes
During study visits, participants completed on paper the Migraine Specific Quality of Life (MSQ) questionnaire version 2.1 [28] (comprising 14 items across three dimensions) and the Migraine Disability Assessment (MIDAS) questionnaire [29] (comprising five retrospective questions measuring headache-related disability as lost time due to headache from paid work or school, household work, and nonwork activities). Participants used an eDiary to record their Preference of Medication (compared with previous medications to treat their pain) and Satisfaction with Medication. Investigators completed a Clinical Global Impression of Change scale [30] on paper, rating the participant’s total improvement relative to the investigator’s past experience with other patients with the same diagnosis, with or without collateral information.
Statistical Analyses
For the current post hoc subgroup analyses, participants who received ≥ 1 dose of rimegepant were analyzed. The data from the three enrollment cohorts were pooled, and then grouped according to history of anxiety (yes or no) and history of depression (yes or no); participants with a history of both anxiety and depression were included in both subgroups. History of anxiety/depression was derived from medical history collected at screening and was based on participant self-report and/or investigator review of the participant’s medical records. Medical histories were coded using MedDRA version 21.1. Similarly, subgroup analyses were conducted based on medication histories and participant-reported use of SSRIs (yes or no) and other antidepressants (yes or no) on or after the start of rimegepant treatment; participants using both SSRIs and other antidepressants were included in both subgroups. Medications were classified by therapeutic class and preferred name using the World Health Organization Drug Dictionary and Anatomical Therapeutic Chemical classification system. Data were summarized by subgroup using descriptive statistics.
Results
Demographics and Clinical Characteristics
Overall, a total of 1800 participants enrolled into PRN 2–8 (n = 1033), PRN 9–14 (n = 481), and scheduled EOD + PRN (n = 286) cohorts were treated with ≥ 1 dose of rimegepant and were included in the current analyses. Their migraine history included a median of 6.0 moderate or severe migraine attacks per month and in 66.7% of participants, the primary migraine type was without aura.
Of the overall population, 35.6% (n = 641) had a history of anxiety and/or depression and 11.2% (n = 202) had histories of both anxiety and depression. The subgroups according to anxiety comprised 23.2% (n = 417) participants with a history of anxiety compared with the remainder of the population (n = 1383) who did not have a history of anxiety. The subgroups according to depression comprised 23.7% (n = 426) participants with a history of depression compared with the remainder of the population (n = 1374) who did not have a history of depression. Anxiety conditions were mostly anxiety (n = 371), post-traumatic stress disorder (n = 27), and generalized anxiety disorder (n = 21), with small numbers of participants with other conditions that included panic attack and obsessive–compulsive disorder (see Table S1 in the electronic supplementary material). Depression conditions were mostly depression (n = 352), major depression (n = 37), and perinatal depression (n = 16), with small numbers of participants with other conditions, including bipolar disorder and seasonal affective disorder (Table S1). Four participants had a history of suicide attempts and one participant had a history of suicidal ideation (Table S1). The proportions of each enrollment cohort who had histories of anxiety or depression were similar (Table S1). Demographics and characteristics were generally comparable across the subgroups according to history of anxiety, and according to history of depression, although participants with these histories (compared with those without these histories) were more often female and White (Table 1).
Table 1.
Demographics and clinical characteristics of the study population
| Anxiety | Depression | SSRI | Other antidepressants | |||||
|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | Yes | No | |
| (n = 417) | (n = 1383) | (n = 426) | (n = 1374) | (n = 181) | (n = 1619) | (n = 195) | (n = 1605) | |
| Age, mean (SD), years | 41.9 (11.96) | 43.4 (12.18) | 43.6 (12.64) | 42.9 (11.99) | 44.9 (12.70) | 42.9 (12.07) | 46.5 (12.38) | 42.7 (12.05) |
| Female, n (%) | 396 (95.0) | 1213 (87.7) | 400 (93.9) | 1209 (88.0) | 170 (93.9) | 1439 (88.9) | 188 (96.4) | 1421 (88.5) |
| Male, n (%) | 21 (5.0) | 170 (12.3) | 26 (6.1) | 165 (12.0) | 11 (6.1) | 180 (11.1) | 7 (3.6) | 184 (11.5) |
| Race, n (%) | ||||||||
| White | 366 (87.8) | 1109 (80.2) | 370 (86.9) | 1105 (80.4) | 162 (89.5) | 1313 (81.1) | 180 (92.3) | 1295 (80.7) |
| Black or African American | 36 (8.6) | 214 (15.5) | 39 (9.2) | 211 (15.4) | 9 (5.0) | 241 (14.9) | 10 (5.1) | 240 (15.0) |
| American Indian or Alaska Native | 3 (0.7) | 7 (0.5) | 2 (0.5) | 8 (0.6) | 1 (0.6) | 9 (0.6) | 1 (0.5) | 9 (0.6) |
| Asian | 7 (1.7) | 25 (1.8) | 3 (0.7) | 29 (2.1) | 3 (1.7) | 29 (1.8) | 1 (0.5) | 31 (1.9) |
| Native Hawaiian or Other Pacific Islander | 1 (0.2) | 4 (0.3) | 2 (0.5) | 3 (0.2) | 2 (1.1) | 3 (0.2) | 0 | 5 (0.3) |
| Multiple | 4 (1.0) | 24 (1.7) | 10 (2.3) | 18 (1.3) | 4 (2.2) | 24 (1.5) | 3 (1.5) | 25 (1.6) |
| Ethnicity, n (%) | ||||||||
| Hispanic or Latino | 32 (7.7) | 145 (10.5) | 26 (6.1) | 151 (11.0) | 14 (7.7) | 163 (10.1) | 5 (2.6) | 172 (10.7) |
| Not Hispanic or Latino | 385 (92.3) | 1238 (89.5) | 400 (93.9) | 1223 (89.0) | 167 (92.3) | 1456 (89.9) | 190 (97.4) | 1433 (89.3) |
| Body mass index, kg/m2 | ||||||||
| n | 415 | 1379 | 424 | 1370 | 181 | 1613 | 193 | 1601 |
| Mean (SD) | 29.8 (7.43) | 29.3 (7.48) | 30.3 (7.85) | 29.1 (7.33) | 29.4 (6.99) | 29.4 (7.53) | 29.9 (7.88) | 29.3 (7.42) |
SD standard deviation, SSRI selective serotonin reuptake inhibitor
Of the overall population, 19.1% (n = 344) were using an SSRI and/or other antidepressants, and 1.8% (n = 32) were taking both an SSRI and other antidepressants. The subgroups according to SSRI use comprised 10.1% (n = 181) participants who were using an SSRI compared with the remainder of the population (n = 1619) who were not. The subgroups according to other antidepressants use comprised 10.8% (n = 195) participants who were using other antidepressants compared with the remainder of the population (n = 1605) who were not. The most commonly used SSRIs were citalopram and sertraline; the most commonly used other antidepressants were bupropion hydrochloride and trazodone (see Table S2 in the electronic supplementary material). Demographics and characteristics were generally comparable across the subgroups according to SSRI use, and according to other antidepressant use, although participants using SSRIs/antidepressants (compared with those not using these treatments) were more often female and White (Table 1). Preventive migraine medication was most often topiramate (Table S2).
Exposure
The median duration of rimegepant treatment overall was 47.3 weeks, with a median average rimegepant exposure per 4 weeks of 6.5 doses. The average rimegepant exposure was similar regardless of a history of anxiety or depression but was somewhat higher in the subgroup taking SSRIs compared with those who were not taking SSRIs (Table 2).
Table 2.
Exposure to rimegepant during study
| Anxiety | Depression | SSRI | Other antidepressants | |||||
|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | Yes | No | |
| (n = 417) | (n = 1383) | (n = 426) | (n = 1374) | (n = 181) | (n = 1619) | (n = 195) | (n = 1605) | |
| Time on rimegepant, weeks | ||||||||
| Mean (SD) | 34.7 (18.95) | 33.6 (19.25) | 33.5 (19.46) | 34.0 (19.10) | 34.4 (18.90) | 33.8 (19.22) | 35.3 (19.30) | 33.7 (19.17) |
| Median | 47.7 | 47.1 | 47.1 | 47.4 | 47.1 | 47.4 | 49.0 | 47.0 |
| Minimum, maximum | 0.1, 54.9 | 0.1, 55.3 | 0.1, 54.9 | 0.1, 55.3 | 0.1, 53.3 | 0.1, 55.3 | 0.1, 53.0 | 0.1, 55.3 |
| Average rimegepant exposure, tablets per 4 weeks | ||||||||
| Mean (SD) | 7.4 (4.44) | 7.8 (4.69) | 7.8 (4.77) | 7.6 (4.59) | 8.3 (4.82) | 7.6 (4.61) | 7.9 (4.82) | 7.6 (4.61) |
| Median | 6.4 | 6.5 | 6.6 | 6.4 | 7.5 | 6.4 | 6.9 | 6.4 |
| Minimum, maximum | 0.3, 20.6 | 0.2, 27.6 | 0.3, 27.6 | 0.2, 27.2 | 0.5, 26.4 | 0.2, 27.6 | 0.3, 22.1 | 0.2, 27.6 |
| Participants taking ≥ 8 tablets per 4 weeks, n (%) | 158 (37.9) | 540 (39.0) | 168 (39.4) | 530 (38.6) | 85 (47.0) | 613 (37.9) | 78 (40.0) | 620 (38.6) |
| Cumulative rimegepant exposure, tablets | ||||||||
| Mean (SD) | 61.7 (46.89) | 62.4 (48.88) | 62.6 (52.15) | 62.1 (47.22) | 68.2 (54.30) | 61.6 (47.69) | 65.8 (47.97) | 61.8 (48.47) |
| Median | 48.0 | 50.0 | 50.0 | 49.0 | 52.0 | 49.0 | 54.0 | 49.0 |
| Minimum, maximum | 1.0, 271.0 | 1.0, 359.0 | 1.0, 359.0 | 1.0, 355.0 | 1.0, 346.0 | 1.0, 359.0 | 1.0, 271.0 | 1.0, 359.0 |
SD standard deviation, SSRI selective serotonin reuptake inhibitor
Adverse Events
Overall, 60.4% of participants reported ≥ 1 AE (Table 3). The proportion of participants reporting AEs was consistent across the subgroups. AEs were reported by 67.1%, 58.4%, 62.0%, and 60.0% of participants in the subgroups with anxiety, without anxiety, with depression, and without depression, respectively, and by 64.1%, 60.0%, 66.2%, and 59.8% of participants in the subgroups using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively (Table 3). The most common AE was upper respiratory tract infection, occurring in 7.7–10.6% of participants across all subgroups (Table 4). The majority of AEs were mild or moderate in intensity (Table 3). The proportion of participants reporting severe AEs was consistent across the subgroups. Severe AEs were reported by 4.3%, 4.4%, 5.4%, and 4.1% of participants in the subgroups with anxiety, without anxiety, with depression, and without depression, respectively, and by 6.6%, 4.1%, 6.2%, and 4.2% of participants in the subgroups using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively (Table 3).
Table 3.
Summary of on-treatment AEs
| Anxiety | Depression | SSRI | Other antidepressants | Overalla | |||||
|---|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | Yes | No | ||
| (n = 417) | (n = 1383) | (n = 426) | (n = 1374) | (n = 181) | (n = 1619) | (n = 195) | (n = 1605) | (N = 1800) | |
| AE | 280 (67.1) | 808 (58.4) | 264 (62.0) | 824 (60.0) | 116 (64.1) | 972 (60.0) | 129 (66.2) | 959 (59.8) | 1088 (60.4) |
| Mild AE | 200 (48.0) | 576 (41.6) | 190 (44.6) | 586 (42.6) | 79 (43.6) | 697 (43.1) | 91 (46.7) | 685 (42.7) | 776 (43.1) |
| Moderate AE | 171 (41.0) | 471 (34.1) | 162 (38.0) | 480 (34.9) | 79 (43.6) | 563 (34.8) | 78 (40.0) | 564 (35.1) | 642 (35.7) |
| Severe AE | 18 (4.3) | 61 (4.4) | 23 (5.4) | 56 (4.1) | 12 (6.6) | 67 (4.1) | 12 (6.2) | 67 (4.2) | 79 (4.4) |
| SAE | 15 (3.6) | 32 (2.3) | 12 (2.8) | 35 (2.5) | 6 (3.3) | 41 (2.5) | 10 (5.1) | 37 (2.3) | 47 (2.6) |
| AE related to study drug | 94 (22.5) | 266 (19.2) | 84 (19.7) | 276 (20.1) | 43 (23.8) | 317 (19.6) | 35 (17.9) | 325 (20.2) | 360 (20.0) |
| SAE related to study drug | 4 (1.0) | 6 (0.4) | 3 (0.7) | 7 (0.5) | 1 (0.6) | 9 (0.6) | 1 (0.5) | 9 (0.6) | 10 (0.6) |
| AE leading to discontinuation of study drug | 17 (4.1) | 31 (2.2) | 13 (3.1) | 35 (2.5) | 9 (5.0) | 39 (2.4) | 6 (3.1) | 42 (2.6) | 48 (2.7) |
| Suicidality AE | 3 (0.7) | 0 | 2 (0.5) | 1 (0.1) | 3 (1.7) | 0 | 0 | 3 (0.2) | 3 (0.2) |
AE adverse event, SAE serious adverse event, SSRI selective serotonin reuptake inhibitor
Data are number (%) of participants with ≥ 1 AE
aSome of the data for the overall population were published previously [24]
Table 4.
Participants with on-treatment AEs (≥ 2% of participants in any subgroup)
| Preferred term | Anxiety | Depression | SSRI | Other antidepressants | Overalla | ||||
|---|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | Yes | No | ||
| (n = 417) | (n = 1383) | (n = 426) | (n = 1374) | (n = 181) | (n = 1619) | (n = 195) | (n = 1605) | (N = 1800) | |
| Upper respiratory tract infection | 44 (10.6) | 114 (8.2) | 41 (9.6) | 117 (8.5) | 14 (7.7) | 144 (8.9) | 20 (10.3) | 138 (8.6) | 158 (8.8) |
| Nasopharyngitis | 24 (5.8) | 98 (7.1) | 31 (7.3) | 91 (6.6) | 9 (5.0) | 113 (7.0) | 19 (9.7) | 103 (6.4) | 122 (6.8) |
| Sinusitis | 24 (5.8) | 68 (4.9) | 28 (6.6) | 64 (4.7) | 10 (5.5) | 82 (5.1) | 10 (5.1) | 82 (5.1) | 92 (5.1) |
| Urinary tract infection | 22 (5.3) | 47 (3.4) | 19 (4.5) | 50 (3.6) | 11 (6.1) | 58 (3.6) | 9 (4.6) | 60 (3.7) | 69 (3.8) |
| Influenza | 16 (3.8) | 43 (3.1) | 21 (4.9) | 38 (2.8) | 7 (3.9) | 52 (3.2) | 13 (6.7) | 46 (2.9) | 59 (3.3) |
| Back pain | 13 (3.1) | 43 (3.1) | 11 (2.6) | 45 (3.3) | 6 (3.3) | 50 (3.1) | 10 (5.1) | 46 (2.9) | 56 (3.1) |
| Bronchitis | 13 (3.1) | 40 (2.9) | 17 (4.0) | 36 (2.6) | 9 (5.0) | 44 (2.7) | 5 (2.6) | 48 (3.0) | 53 (2.9) |
| Nausea | 20 (4.8) | 31 (2.2) | 12 (2.8) | 39 (2.8) | 8 (4.4) | 43 (2.7) | 6 (3.1) | 45 (2.8) | 51 (2.8) |
| Dizziness | 14 (3.4) | 28 (2.0) | 9 (2.1) | 33 (2.4) | 2 (1.1) | 40 (2.5) | 4 (2.1) | 38 (2.4) | 42 (2.3) |
| Arthralgia | 8 (1.9) | 28 (2.0) | 9 (2.1) | 27 (2.0) | 4 (2.2) | 32 (2.0) | 5 (2.6) | 31 (1.9) | 36 (2.0) |
| Diarrhea | 11 (2.6) | 23 (1.7) | 8 (1.9) | 26 (1.9) | 2 (1.1) | 32 (2.0) | 8 (4.1) | 26 (1.6) | 34 (1.9) |
| Constipation | 4 (1.0) | 25 (1.8) | 9 (2.1) | 20 (1.5) | 4 (2.2) | 25 (1.5) | 2 (1.0) | 27 (1.7) | 29 (1.6) |
| Pharyngitis streptococcal | 6 (1.4) | 20 (1.4) | 7 (1.6) | 19 (1.4) | 3 (1.7) | 23 (1.4) | 4 (2.1) | 22 (1.4) | 26 (1.4) |
| Cough | 7 (1.7) | 18 (1.3) | 3 (0.7) | 22 (1.6) | 2 (1.1) | 23 (1.4) | 5 (2.6) | 20 (1.2) | 25 (1.4) |
| Sinus congestion | 10 (2.4) | 14 (1.0) | 7 (1.6) | 17 (1.2) | 1 (0.6) | 23 (1.4) | 1 (0.5) | 23 (1.4) | 24 (1.3) |
| Vomiting | 9 (2.2) | 14 (1.0) | 4 (0.9) | 19 (1.4) | 2 (1.1) | 21 (1.3) | 3 (1.5) | 20 (1.2) | 23 (1.3) |
| Somnolence | 11 (2.6) | 12 (0.9) | 6 (1.4) | 17 (1.2) | 4 (2.2) | 19 (1.2) | 2 (1.0) | 21 (1.3) | 23 (1.3) |
| Myalgia | 5 (1.2) | 18 (1.3) | 5 (1.2) | 18 (1.3) | 4 (2.2) | 19 (1.2) | 3 (1.5) | 20 (1.2) | 23 (1.3) |
| Procedural pain | 5 (1.2) | 18 (1.3) | 7 (1.6) | 16 (1.2) | 4 (2.2) | 19 (1.2) | 3 (1.5) | 20 (1.2) | 23 (1.3) |
| Anxiety | 8 (1.9) | 15 (1.1) | 6 (1.4) | 17 (1.2) | 5 (2.8) | 18 (1.1) | 5 (2.6) | 18 (1.1) | 23 (1.3) |
| Neck pain | 4 (1.0) | 18 (1.3) | 3 (0.7) | 19 (1.4) | 3 (1.7) | 19 (1.2) | 4 (2.1) | 18 (1.1) | 22 (1.2) |
| Viral upper respiratory tract infection | 9 (2.2) | 11 (0.8) | 8 (1.9) | 12 (0.9) | 6 (3.3) | 14 (0.9) | 6 (3.1) | 14 (0.9) | 20 (1.1) |
| Ligament sprain | 8 (1.9) | 12 (0.9) | 7 (1.6) | 13 (0.9) | 4 (2.2) | 16 (1.0) | 2 (1.0) | 18 (1.1) | 20 (1.1) |
| Ear infection | 4 (1.0) | 15 (1.1) | 5 (1.2) | 14 (1.0) | 1 (0.6) | 18 (1.1) | 6 (3.1) | 13 (0.8) | 19 (1.1) |
| Muscle strain | 6 (1.4) | 12 (0.9) | 5 (1.2) | 13 (0.9) | 3 (1.7) | 15 (0.9) | 4 (2.1) | 14 (0.9) | 18 (1.0) |
| Insomnia | 4 (1.0) | 12 (0.9) | 7 (1.6) | 9 (0.7) | 4 (2.2) | 12 (0.7) | 0 | 16 (1.0) | 16 (0.9) |
| Contusion | 6 (1.4) | 10 (0.7) | 11 (2.6) | 5 (0.4) | 3 (1.7) | 13 (0.8) | 4 (2.1) | 12 (0.7) | 16 (0.9) |
| Pain | 2 (0.5) | 12 (0.9) | 6 (1.4) | 8 (0.6) | 4 (2.2) | 10 (0.6) | 0 | 14 (0.9) | 14 (0.8) |
| Musculoskeletal pain | 3 (0.7) | 11 (0.8) | 2 (0.5) | 12 (0.9) | 0 | 14 (0.9) | 4 (2.1) | 10 (0.6) | 14 (0.8) |
AE adverse event, SSRI selective serotonin reuptake inhibitor
Data are number (%) of participants. All preferred terms reported in ≥ 2% of participants in any subgroup are shown, listed in descending order of frequency in the overall population
aSome of the data for the overall population were published previously [24]
There were no deaths, and there were no documented cases of serotonin syndrome during the study. The proportion of participants reporting SAEs was consistent across the subgroups. SAEs were reported by 3.6%, 2.3%, 2.8%, and 2.5% of participants in the subgroups with anxiety, without anxiety, with depression, and without depression, respectively, and by 3.3%, 2.5%, 5.1%, and 2.3% of participants in the subgroups using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively (Table 3). Among participants with a history of anxiety and/or depression, or who were using SSRIs and/or other antidepressants, few SAEs occurred in > 1 participant (see Table S3 in the electronic supplementary material). Most SAEs were not considered by investigators to be related to the study drug (Table 3).
The proportion of participants reporting AEs leading to discontinuation of study drug was low. Discontinuation of rimegepant due to AEs was reported by 4.1%, 2.2%, 3.1%, and 2.5% of participants in the subgroups with anxiety, without anxiety, with depression, and without depression, respectively, and by 5.0%, 2.4%, 3.1%, and 2.6% of participants in the subgroups using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively (Table 3).
S-STS
The S-STS total score was zero at baseline (1799/1799 participants) and did not change during the on-treatment period for 99.4% (1750/1761) of participants. On-treatment worsening from baseline (responses > 0) for the total score was reported in 11 participants overall during the long-term treatment period: they were discontinued from the study for a positive S-STS score > 0 (n = 1), were discontinued for AEs of anxiety (n = 1), suicidal ideation (n = 1), or seasonal affective disorder (n = 1), withdrew from the study (n = 2), completed the study (n = 3), or did not complete the study due to noncompliance (n = 2).
Suicidality AEs
Suicidality AEs were reported in three participants overall during the on-treatment period (0.2%, 3/1800), all of whom had anxiety and/or depression and were taking SSRIs (Table 3), comprising 0.5% (3/641) of participants with anxiety and/or depression. Two additional participants reported suicidality AEs during the follow-up period. All five suicidality AEs were suicidal ideation; three were SAEs. One was considered unlikely to be related and four were considered to be unrelated to rimegepant. None were in participants in the EOD + PRN cohort. These five suicidality AEs are described below.
Suicidal ideation was reported during the on-treatment period in a participant in the PRN 9–14 cohort. The participant had a medical history of anxiety (ongoing during the study) and depression. The AE of suicidal ideation, mild in intensity, occurred on day 33 and over a 25-day period. The participant had taken 12 doses of rimegepant over a 27-day period, and the AE of suicidal ideation occurred 4 days after the previous dose. The dose of rimegepant was not changed; the AE resolved, and the participant completed the study. The AE was considered by the investigator to be unrelated to rimegepant.
Suicidal ideation was reported during the on-treatment period in a participant in the PRN 2–8 cohort. The participant had a medical history of anxiety (ongoing during the study), depression, and panic attacks. The AE of suicidal ideation, mild in intensity, occurred on day 63 and concurrently with depression. The participant had taken eight doses of rimegepant over a 22-day period, and the AE of suicidal ideation occurred 14 days after the previous dose. Rimegepant was withdrawn and the participant was discontinued from the study, with the AE ongoing at that time. The AE was considered by the investigator to be unrelated to rimegepant.
Suicidal ideation was reported during the on-treatment period in a participant in the PRN 2–8 cohort. The participant had a medical history of anxiety (ongoing during the study). The SAE of suicidal ideation, moderate in intensity, occurred on day 62 and over 3 days. The participant had taken three doses of rimegepant over a 13-day period, and the SAE of suicidal ideation occurred 1 day after the previous dose. Rimegepant was withdrawn, the participant was discontinued from the study, and the SAE had resolved at that time. The SAE was considered by the investigator unlikely to be related to rimegepant.
During the follow-up period, there were two further reports of suicidal ideation, both in participants in the PRN 2–8 cohort. The first participant with a suicidal ideation SAE during the follow-up period had a medical history of depression and generalized anxiety disorder (both ongoing during the study), major depression, and suicide attempt. The SAE of suicidal ideation, moderate in intensity, occurred on day 220 and over 7 days during the follow-up period, concurrently with anxiety, depression, and post-traumatic stress disorder. The participant had taken an average of 2.7 doses of rimegepant/4 weeks over a 196-day period, and the SAE of suicidal ideation occurred 15 days after the previous dose. The SAE was considered resolved on day 7. The SAE was considered by the investigator to be unrelated to rimegepant. The second participant with a suicidal ideation SAE during the follow-up period had a medical history of suicidal ideation, suicide attempts, post-traumatic stress disorder (ongoing during the study), and bipolar I disorder (ongoing during the study). The SAE of suicidal ideation, moderate in intensity, occurred on day 43 and over 15 days during the follow-up period, concurrently with post-traumatic stress disorder and bipolar I disorder. The participant had taken 12 doses of rimegepant over a 27-day period, and the AE of suicidal ideation occurred 8 days after the previous dose. The SAE was considered resolved on day 15. The SAE was considered by the investigator to be unrelated to rimegepant.
Liver Function Tests
A small number of participants overall (< 1%) had clinically significant transaminase elevations (Table 5). There were no clear differences between subgroups, although the small number of events precludes a definitive evaluation.
Table 5.
Participants with on-treatment clinically significant liver function test abnormalities
| Anxiety | Depression | SSRI | Other antidepressants | Overall | |||||
|---|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | Yes | No | ||
| (n = 417) | (n = 1383) | (n = 426) | (n = 1374) | (n = 181) | (n = 1619) | (n = 195) | (n = 1605) | (N = 1800) | |
| Sample size, n | 411 | 1351 | 418 | 1344 | 179 | 1583 | 192 | 1570 | 1762 |
| Alanine aminotransferase | |||||||||
| Grade 0 | 381 (92.7) | 1226 (90.7) | 380 (90.9) | 1227 (91.3) | 162 (90.5) | 1445 (91.3) | 178 (92.7) | 1429 (91.0) | 1607 (91.2) |
| Grade 1–2 | 26 (6.3) | 124 (9.2) | 37 (8.9) | 113 (8.4) | 16 (8.9) | 134 (8.5) | 13 (6.8) | 137 (8.7) | 150 (8.5) |
| Grade 3–4a | 4 (1.0) | 1 (0.1) | 1 (0.2) | 4 (0.3) | 1 (0.6) | 4 (0.3) | 1 (0.5) | 4 (0.3) | 5 (0.3) |
| Aspartate aminotransferase | |||||||||
| Grade 0 | 380 (92.5) | 1264 (93.6) | 390 (93.3) | 1254 (93.3) | 163 (91.1) | 1481 (93.6) | 180 (93.8) | 1464 (93.2) | 1644 (93.3) |
| Grade 1–2 | 28 (6.8) | 84 (6.2) | 26 (6.2) | 86 (6.4) | 16 (8.9) | 96 (6.1) | 12 (6.3) | 100 (6.4) | 112 (6.4) |
| Grade 3–4a | 3 (0.7) | 3 (0.2) | 2 (0.5) | 4 (0.3) | 0 | 6 (0.4) | 0 | 6 (0.4) | 6 (0.3) |
| Alkaline phosphatase | |||||||||
| Grade 0 | 402 (97.8) | 1320 (97.7) | 407 (97.4) | 1315 (97.8) | 173 (96.6) | 1549 (97.9) | 187 (97.4) | 1535 (97.8) | 1722 (97.7) |
| Grade 1–2 | 9 (2.2) | 31 (2.3) | 11 (2.6) | 29 (2.2) | 6 (3.4) | 34 (2.1) | 5 (2.6) | 35 (2.2) | 40 (2.3) |
| Grade 3–4a | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
SSRI selective serotonin reuptake inhibitor
Data are number (%) of participants. Percentages are based on the number of participants with non-missing data at an on-treatment visit (n). Worst abnormality. Toxicity scale: Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
aGrade 3 or 4 is clinically significant
Other Outcomes
Improvements from baseline were evident across all subgroups at week 12 and week 52, for all three dimensions of the MSQ (Table 6) and MIDAS total scores (see Table S4 in the electronic supplementary material). There were some differences in participants’ medication preference between yes/no subgroups suggested at week 12, with smaller proportions of participants with depression, SSRI use, or other antidepressant use preferring rimegepant (much better or slightly better than their previous medication) compared with the respective “no” subgroups; these differences were smaller at week 52 (see Table S5 in the electronic supplementary material). Across most subgroups at week 12 and all subgroups at week 52, the majority of participants were satisfied (completely or very) by their medication and few were dissatisfied (completely or very) (see Table S6 in the electronic supplementary material), and in terms of Clinical Global Impression of Change, investigators rated the majority of participants improved (very much or much) and few were rated worse (very much or much) (see Table S7 in the electronic supplementary material).
Table 6.
Change from baseline in MSQ at week 12 and week 52
| Anxiety | Depression | SSRI | Other antidepressants | |||||
|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | Yes | No | |
| (n = 417) | (n = 1383) | (n = 426) | (n = 1374) | (n = 181) | (n = 1619) | (n = 195) | (n = 1605) | |
| Role restrictive | ||||||||
| Baseline, n | 416 | 1381 | 425 | 1372 | 180 | 1617 | 195 | 1602 |
| Mean (SD) | 50.2 (18.43) | 53.5 (18.26) | 50.6 (17.32) | 53.4 (18.60) | 52.3 (16.60) | 52.7 (18.53) | 51.3 (17.95) | 52.9 (18.39) |
| Week 12, n | 378 | 1266 | 381 | 1263 | 164 | 1480 | 173 | 1471 |
| Mean (SD) | 66.0 (18.84) | 67.8 (18.79) | 65.5 (18.16) | 68.0 (18.97) | 64.4 (17.68) | 67.7 (18.91) | 64.6 (19.63) | 67.7 (18.69) |
| Change from baseline at week 12, n | 377 | 1264 | 380 | 1261 | 163 | 1478 | 173 | 1468 |
| Mean (SD) | 15.4 (20.04) | 14.2 (19.41) | 14.5 (19.76) | 14.4 (19.50) | 11.4 (18.20) | 14.8 (19.67) | 13.6 (19.94) | 14.6 (19.51) |
| 95% CI | 13.36, 17.42 | 13.12, 15.26 | 12.54, 16.53 | 13.37, 15.52 | 8.58, 14.21 | 13.80, 15.81 | 10.58, 16.57 | 13.57, 15.57 |
| Week 52, n | 241 | 740 | 233 | 748 | 101 | 880 | 116 | 865 |
| Mean (SD) | 69.9 (18.58) | 71.7 (19.52) | 68.7 (19.40) | 72.0 (19.21) | 66.5 (19.40) | 71.8 (19.22) | 68.4 (19.99) | 71.6 (19.18) |
| Change from baseline at week 52, n | 240 | 740 | 232 | 748 | 100 | 880 | 116 | 864 |
| Mean (SD) | 18.7 (19.97) | 17.4 (20.46) | 18.0 (20.87) | 17.7 (20.19) | 15.0 (22.09) | 18.1 (20.12) | 16.7 (18.56) | 17.9 (20.58) |
| 95% CI | 16.16, 21.24 | 15.97, 18.92 | 15.28, 20.68 | 16.24, 19.13 | 10.62, 19.38 | 16.74, 19.40 | 13.29, 20.11 | 16.52, 19.27 |
| Role preventive | ||||||||
| Baseline, n | 416 | 1381 | 425 | 1372 | 180 | 1617 | 195 | 1602 |
| Mean (SD) | 64.5 (21.24) | 68.9 (20.17) | 65.7 (19.97) | 68.6 (20.62) | 68.7 (18.98) | 67.8 (20.67) | 66.5 (18.33) | 68.1 (20.75) |
| Week 12, n | 378 | 1266 | 381 | 1263 | 164 | 1480 | 173 | 1471 |
| Mean (SD) | 77.7 (18.43) | 80.2 (18.31) | 78.1 (17.87) | 80.1 (18.49) | 78.8 (16.51) | 79.7 (18.56) | 77.4 (19.79) | 79.9 (18.18) |
| Change from baseline at week 12, n | 377 | 1264 | 380 | 1261 | 163 | 1478 | 173 | 1468 |
| Mean (SD) | 12.9 (20.09) | 11.1 (19.74) | 12.1 (19.89) | 11.4 (19.82) | 9.4 (16.79) | 11.8 (20.13) | 10.9 (20.77) | 11.6 (19.72) |
| 95% CI | 10.86, 14.93 | 10.04, 12.22 | 10.11, 14.12 | 10.26, 12.45 | 6.82, 12.01 | 10.74, 12.79 | 7.75, 13.98 | 10.60, 12.62 |
| Week 52, n | 241 | 740 | 233 | 748 | 101 | 880 | 116 | 865 |
| Mean (SD) | 81.4 (16.17) | 83.4 (17.39) | 80.6 (16.95) | 83.7 (17.11) | 79.9 (16.58) | 83.3 (17.15) | 80.7 (17.90) | 83.2 (17.00) |
| Change from baseline at week 52, n | 240 | 740 | 232 | 748 | 100 | 880 | 116 | 864 |
| Mean (SD) | 16.3 (20.41) | 13.8 (20.26) | 15.3 (21.28) | 14.1 (20.01) | 11.2 (19.55) | 14.8 (20.38) | 14.2 (19.83) | 14.4 (20.39) |
| 95% CI | 13.74, 18.93 | 12.33, 15.25 | 12.57, 18.08 | 12.69, 15.57 | 7.32, 15.08 | 13.43, 16.13 | 10.58, 17.87 | 13.08, 15.80 |
| Emotional function | ||||||||
| Baseline, n | 416 | 1381 | 425 | 1372 | 180 | 1617 | 195 | 1602 |
| Mean (SD) | 57.3 (26.42) | 62.0 (25.78) | 58.1 (25.96) | 61.8 (25.96) | 60.8 (23.76) | 60.9 (26.24) | 59.2 (24.80) | 61.1 (26.14) |
| Week 12, n | 378 | 1266 | 381 | 1263 | 164 | 1480 | 173 | 1471 |
| Mean (SD) | 74.1 (24.02) | 77.2 (23.24) | 73.9 (24.49) | 77.3 (23.08) | 75.5 (21.54) | 76.6 (23.66) | 72.3 (26.90) | 77.0 (22.97) |
| Change from baseline at week 12, n | 377 | 1264 | 380 | 1261 | 163 | 1478 | 173 | 1468 |
| Mean (SD) | 16.3 (24.69) | 15.1 (23.29) | 15.2 (25.03) | 15.5 (23.19) | 13.5 (22.19) | 15.6 (23.77) | 12.1 (24.75) | 15.8 (23.46) |
| 95% CI | 13.80, 18.80 | 13.85, 16.42 | 12.70, 17.75 | 14.17, 16.73 | 10.11, 16.97 | 14.39, 16.82 | 8.39, 15.81 | 14.59, 16.99 |
| Week 52, n | 241 | 740 | 233 | 748 | 101 | 880 | 116 | 865 |
| Mean (SD) | 77.6 (22.55) | 80.1 (23.12) | 77.5 (22.95) | 80.1 (22.99) | 76.3 (20.67) | 79.9 (23.23) | 75.9 (24.42) | 80.0 (22.77) |
| Change from baseline at week 52, n | 240 | 740 | 232 | 748 | 100 | 880 | 116 | 864 |
| Mean (SD) | 17.1 (28.03) | 17.4 (25.40) | 18.0 (28.55) | 17.1 (25.25) | 13.8 (25.27) | 17.7 (26.12) | 12.1 (26.27) | 18.0 (25.96) |
| 95% CI | 13.49, 20.62 | 15.59, 19.26 | 14.27, 21.65 | 15.33, 18.95 | 8.79, 18.81 | 16.01, 19.46 | 7.24, 16.90 | 16.31, 19.77 |
CI confidence interval, MSQ Migraine Specific Quality of Life Questionnaire v2.1, SD standard deviation, SSRI selective serotonin reuptake inhibitor
Discussion
These analyses showed that rimegepant was generally safe and well tolerated for the acute treatment of migraine when administered for up to 1 year in adults with a history of anxiety and/or depression, or who were using SSRIs or other antidepressants.
The incidences of AEs, SAEs, and discontinuations from treatment due to AEs in participants with migraine and a self-reported history of anxiety and/or depression were similar to those seen for the subgroups without these histories, and were also similar regardless of the use of SSRIs (most often citalopram or sertraline) or other antidepressants (most often bupropion hydrochloride or trazodone). Key study exclusion criteria were current diagnoses of major depressive disorder, schizophrenia, bipolar disorder, or borderline personality disorder, and atypical antipsychotics and valproic acid/valproate were not permitted during the study.
Treatment options for migraine can be limited for patients with comorbid anxiety or depression, especially if they are taking SSRIs, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. The current subgroup analyses support the safety of rimegepant in participants taking SSRIs or other antidepressants. There were no cases of serotonin syndrome, which is a potential concern when a triptan is prescribed for the acute treatment of migraine on a background of SSRIs or other antidepressants with serotonergic mechanisms. There were no deaths and no suicide attempts. During the year-long study and follow-up period, there were five reports of suicidal ideation amongst an overall population of 1800 participants with migraine. All five participants had psychiatric conditions, underlying the importance of evaluating patients with migraine for psychiatric comorbidities. The two reports of suicidal ideation that occurred during the follow-up period were in participants with a history of suicide attempt amongst other psychiatric comorbidities. Due to regulatory guidance, suicidality AEs were prespecified events of special interest for the study, so the investigators were specifically looking for them and assessing the participant using the S-STS at each study visit. Comparing the prevalence of suicidal ideation during the current study of up to 1 years’ duration with published estimates for people with migraine and the general population is complicated by the different assessment tools and time frames used [9, 10, 31].
The overall study population was representative of the real-world migraine patient population, which is predominantly female and varied in age [32, 33]. Of the current overall migraine population, 23.2% had self-reported anxiety and 23.7% had self-reported depression, within the range of published estimates of 13.2–76.4% for generalized anxiety disorder [2] and 5.6–73.7% for depression [2], although diagnostic criteria, study designs, and populations vary. The study was not designed to monitor anxiety or depression, but improvements in the emotional function dimension of the MSQ and other patient-reported outcomes suggest that rimegepant may be associated with improved outcomes of mental health measures. This observation is perhaps secondary to more effective acute treatment of migraine attacks, as suggested by positive medication preference and treatment satisfaction scores.
The current safety data specific to patients with migraine and comorbid anxiety and/or depression provide important information pertaining to the safe use of rimegepant and add to the knowledge base for the oral, small molecule CGRP receptor antagonists. The efficacy of CGRP pathway-targeted monoclonal antibodies, which require subcutaneous or intravenous administration, has been reported for patients with migraine and comorbid anxiety or depression [34–36], and impacts on psychiatric comorbidities have been reported [37, 38], but few safety data have been published that are specific to that population.
This study had some limitations, including the inherent risk of bias associated with open-label and non-controlled studies. The analyses were post hoc, so the data should be considered cautiously. The study could not prospectively assess serotonin syndrome: although there were no documented cases of serotonin syndrome (based on retrospective review of preferred terms), the frequencies of preferred terms that could be signs and symptoms of subclinical serotonin syndrome were too small for meaningful analyses and were confounded by psychiatric history in these subgroups. Similarly, the study could not assess subgroup differences in other infrequent AEs. The study was not designed to specifically monitor anxiety or depression symptoms, and validated evaluation tools were not incorporated into the study design: investigators determined if there was a history of anxiety or depression based on the individual’s self-report and/or their medical records. Additionally, participants with a major depressive diagnosis, a recent major depressive disorder episode, and other more clinically significant psychiatric disorders were excluded from the study. Therefore, the generalizability of these results to a more severely impacted population is limited.
Conclusions
Rimegepant 75 mg administered for up to 52 weeks demonstrated favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression, and in those using an SSRI and/or other antidepressants.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the participants of the study for their contributions to this research.
Medical Writing/Editorial Assistance
Medical writing support was provided by Kim Russell, PhD, of Engage Scientific Solutions and was funded by Pfizer.
Author Contributions
David Kudrow is an investigator for the rimegepant clinical development program. David Kudrow, Susan Hutchinson, Glenn C. Pixton, and Terence Fullerton contributed to the acquisition, analysis, or interpretation of data. David Kudrow, Susan Hutchinson, Glenn C. Pixton, and Terence Fullerton contributed to drafting the manuscript or reviewing it critically for important intellectual content. David Kudrow, Susan Hutchinson, Glenn C. Pixton, and Terence Fullerton approved the final version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
This study was sponsored by Biohaven, which was acquired by Pfizer in October 2022. The journal’s Rapid Service Fee was funded by Pfizer.
Data Availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
Declarations
Conflict of Interest
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. David Kudrow reports research grants from Pfizer, Lilly, Aeon, AbbVie, and Biohaven; speakers bureau for AbbVie; and serving on advisory boards for Lundbeck and AbbVie. Susan Hutchinson has served as a consultant for AbbVie, Astellas, Biohaven, Impel, Lilly, Lundbeck Teva, Theranica, and Upsher-Smith. She is on the speakers bureau for AbbVie, Astellas, Impel, Lilly, and Lundbeck. Glenn C. Pixton is an employee of Pfizer and owns stock/stock options in Pfizer, and owns stock in AbbVie. Terence Fullerton is an employee of Pfizer and owns stock/stock options in Pfizer.
Ethical Approval
The study was conducted in accordance with Good Clinical Practice, as defined by the International Conference on Harmonisation, Good Laboratory Practice, the Declaration of Helsinki, and all applicable regulations. Prior to the study, all participants provided written informed consent, and the protocol received Institutional Review Board approval (Advarra IRB [IRB00000971], Schulman Associates IRB [IRB00007642; acquired by Advarra], and Biomedical Research Alliance New York [BRANY] IRB [IRB00000080]).
Footnotes
Prior Presentation: Some of these data were presented at the 62nd Annual Scientific Meeting of the American Headache Society, June 4–7, 2020, San Diego, California.
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Supplementary Materials
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.